There has been considerable interest within the pharmaceutical industry in the development of dosage forms which provide for the controlled release of beneficial substances over a period of time. Releasing an active substance in this way can help to improve bioavailability and ensure that appropriate concentrations of the substance are provided for a sustained period without the need for repeated dosing. In turn, this also helps to minimise the effects of patient non-compliance which is frequently an issue with other forms of administration.
Generally speaking, controlled release formulations are based on polymer material systems. Commonly, the active ingredients are incorporated into polymer and sol-gel systems by entrapment during synthesis of the matrix phase. Microencapsulation techniques for biodegradable polymers include such methods as film casting, moulding, spray drying and extrusion, melt dispersion, interfacial deposition, phase separation by emulsification and solvent evaporation, air suspension coating, pan coating and in-situ polymerization. Melt dispersion techniques are described, for example, in U.S. Pat. No. 5,807,574 and U.S. Pat. No. 5,665,428.
Less commonly, the active ingredient is loaded after formation of the porous matrix is complete. Such carrier systems generally have micron-sized rather than nanometer-sized pores. U.S. Pat. No. 6,238,705, for example, describes the loading of macroporous polymer compositions by simple soaking in a solution of the active ingredient and U.S. Pat. Nos. 5,665,114 and 6,521,284 disclose the use of pressure to load the pores of implantable prostheses made of polytetrafluoroethene (PTFE).
The problem of achieving high loading of the active ingredient limits the effectiveness of many currently known polymer based delivery systems. Various approaches to overcoming this issue have been described. U.S. Pat. No. 5,718,922, for example, discloses forming drug microspheres in a polymer/oil dispersion with a hydrophilic drug suspended in the oil phase, the oil preventing partition during microsphere formation such that a high drug loading can be achieved. In U.S. Pat. No. 6,319,381 there is described a technique for loading drugs into a porous metal prosthesis such as a stent. Here, the drug is first added to a first fluid that is a solvent of high capillary permeation, gross surface deposits are then removed by mechanical agitation in a second fluid that is a non-solvent of low capillary permeation and finally the prosthesis is rinsed in a third fluid that is a solvent for the drug but which once again has a low capillary permeability.
The use of the semiconductor, silicon, in biological applications is known in the literature and is described, for example, in WO 97/06101. Here it is disclosed that certain forms of porous silicon, in particular mesoporous silicon, are resorbable and dissolve over a period of time when immersed in simulated body fluid solution.
To date, the majority of studies relating to impregnation of porous silicon has been in the field of optoelectronic devices and structures. For example porous silicon has been impregnated with conductive material to improve the efficiency of light emitting diodes. Materials that have been incorporated into porous silicon include metals such as nickel, copper, iron, silver, and gold; semiconductors such as germanium, cadmium telluride, zinc selenide, and tin oxide; and polymers such as polypyrrole, polyaniline, polystyrene, and polymethylmethacrylate (PMMA).
As discussed by Herino in Properties of Porous Silicon EMIS Data Review Series, No 18, p 66 to 76 (1997), it has proved difficult to incorporate high concentrations of impregnated substance into relatively large volumes of porous silicon due to blocking of the narrow pores. Deposition of material towards the opening of the pores tends to prevent a high proportion of the material from occupying the pore system.
Zangooie et al in Thin Solid Films 313/4, p 825-830 (1998) report the adsorption of proteins in thin oxidised porous silicon layers. Spectrosopic ellipsometry was used to estimate protein incorporation in the porous silicon, the incorporation process resulting in a change in refractive index of the porous silicon. A volume percentage of adsorbed albumin of 10.7% was reported for 55% porous silicon. The subsequent release of protein was not demonstrated.
Studies on the deposition of solutions of compounds, including small drug molecules, peptides, glycolipids, and carbohydrates, ranging in size from 150 to 12,000 daltons, onto a mesoporous silicon sample surface using a desorption—ionisation technique are reported Wei in Nature (Vol 399, 243-246 (1999)). The concentrations used were extremely low (0.001 to 10 micromolar) and the depth of the penetration of the analytes was not recorded.
High levels of pore filling by germanium, another electronic material, are described by Halimaoui et al in J. Appl. Phys. 78, 3428-30 (1995). However, this involved the use of ultra high vacuum continuous vapour deposition, a technique which would not be suitable for most pharmaceutical applications.
It has been suggested that the properties of porous silicon render it useful as a vehicle for delivering beneficial substances to a subject. Where resorbable porous silicon is associated with a beneficial substance, for example, then resorption of the porous silicon in the body may result in release of the beneficial substance, affording the possibility of controlled release of the beneficial substance disposed in the pores of the porous silicon as a result of corrosion or dissolution of the resorbable silicon. Included within the literature are suggested applications in which the porous silicon is in the form of an implant impregnated with a beneficial substance (as described in WO 99/53898), a tablet or suppository (see, for example WO 01/29529) or alternatively is formulated into a particulate product associated with a beneficial substance for injection through the skin (see WO 01/76564) or for delivery as a dermatological or pulmonary formulation (as described in WO 02/15863 and WO 03/011251 respectively).
Although the potential for using microparticles of porous silicon as a delivery vehicle for a beneficial substance has been mentioned, high loading levels of beneficial substance, especially where the beneficial substance is an organic compound, remain difficult to achieve and no such compositions have been exemplified previously.
WO 03/011251, mentioned above, implies that a desired loading level may be achieved by a process of incubating porous silicon in a solution of the active agent (such that the solution of the active agent penetrates into the pores of the porous silicon by capillary action) and then removing the solvent. In practice, however, this method is generally less suitable for situations where it is required that the beneficial substance is delivered at high doses.
WO 99/53898 discusses the desirability of being able to deliver beneficial substances by means of a silicon implant but states that restrictions on the physical size of the drug payload for implants restricts their use, in practical terms, to delivering microminerals or other substances which are not required at high levels. Loading of porous silicon implants with various metals or compounds of metals by a method involving melting a salt of the metal on the surface of a sample of porous silicon is demonstrated but it is suggested that such a method would not be applicable in the case of large organic drug molecules as thermal degradation would be expected to occur when melting takes place. There would be no motivation, therefore, to look to the method of WO 99/53898 for the delivery of high doses of beneficial organic compounds.
The combination of silicon microparticles with a cytotoxic agent such as 5-fluorouracil is mentioned in WO 02/067998 but there is no disclosure of high loading levels. Moreover, although a number of possible ways of associating the cytotoxic agent with the microparticles are discussed, there is no suggestion that methods involving heating would be appropriate.
There therefore remains a continuing need for the development of improved dosage forms for the controlled release of beneficial organic substances, especially for use in situations where the organic substance is required to be delivered at high doses.